Abstract P027: MUC1-C integrates chronic activation of the type I and II interferon pathways in treatment resistance of triple-negative breast cancer

2021 ◽  
Author(s):  
Nami Yamashita ◽  
Atsushi Fushimi ◽  
Yoshihiro Morimoto ◽  
Atrayee Bhattacharya ◽  
Mark Long ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Treatment Resistance ◽  
Type I ◽  
Chronic Activation

scholarly journals Influence of Germline BRCA Genotype on the Survival of Patients with Triple-Negative Breast Cancer

2021 ◽  
Vol 1 (3) ◽  
pp. 140-147
Author(s):  
Cynthia Villarreal-Garza ◽  
Ana S. Ferrigno ◽  
Alejandro Aranda-Gutierrez ◽  
Paul H. Frankel ◽  
Nora H. Ruel ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Point Mutations ◽  
Treatment Resistance ◽  
Cancer Center ◽  
Breast Cancers ◽  
Entire Cohort ◽  
Pathogenic Variants ◽  
Mutational Status

The presence of BRCA pathogenic variants (PV) in triple-negative breast cancer (TNBC) is associated with a distinctive genomic profile that makes the tumor particularly susceptible to DNA-damaging treatments. However, patients with BRCA PVs can develop treatment resistance through the appearance of reversion mutations and restored BRCA expression. As copy-number variants (CNV) could be less susceptible to reversion mutations than point mutations, we hypothesize that carriers of BRCA CNVs may have improved survival after treatment compared with carriers of other BRCA PVs or BRCA wild-type. Women diagnosed with stage I–III TNBC at ≤50 years at a cancer center in Mexico City were screened for BRCA PVs using a recurrent PV assay (HISPANEL; 77% sensitivity). Recurrence-free survival (RFS) and overall survival (OS) were compared according to the mutational status. Among 180 women, 17 (9%) were carriers of BRCA1 ex9–12del CNVs and 26 (14%) of other BRCA PVs. RFS at ten years for the whole cohort was 79.2% [95% confidence interval (CI), 72.3–84.6], with no significant differences according to mutational status. 10-year OS for the entire cohort was 85.3% (95% CI, 78.7–90.0), with BRCA CNV carriers demonstrating numerically superior OS rates other PV carriers and noncarriers (100% vs. 78.6% and 84.7%; log-rank P = 0.037 and P = 0.051, respectively). This study suggests that BRCA1 ex9–12del CNV carriers with TNBC may have a better OS, and supports the hypothesis that the genotype of BRCA PVs may influence survival by limiting treatment resistance mediated by reversion mutations among CNV carriers. Significance: Large CNV BRCA carriers in a cohort of young Mexican patients with TNBC had superior OS rates than carriers of other BRCA pathogenic variants (i.e., small indels or point mutations). We hypothesize that this is due to the resistance of CNVs to reversion mutations mediating resistance to therapy. If validated, these findings have important prognostic and clinical treatment implications for BRCA-associated breast cancers.

scholarly journals IFI16 inhibits DNA repair that potentiates type-I interferon-induced antitumor effects in triple negative breast cancer

Cell Reports ◽  
2021 ◽  
Vol 37 (12) ◽  
pp. 110138
Author(s):  
Na-Lee Ka ◽  
Ga Young Lim ◽  
Sewon Hwang ◽  
Seung-Su Kim ◽  
Mi-Ock Lee
Keyword(s):  
Breast Cancer ◽  
Dna Repair ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Type I Interferon ◽  
Type I ◽  
Antitumor Effects

A randomized, triple negative breast cancer enrolling trial to confirm molecular profiling improves survival (ARTEMIS).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS590-TPS590 ◽  
Author(s):  
Clinton Yam ◽  
Kenneth R. Hess ◽  
Jennifer Keating Litton ◽  
Wei Tse Yang ◽  
Helen Piwnica-Worms ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trial ◽  
Triple Negative Breast Cancer ◽  
Primary Tumor ◽  
Triple Negative ◽  
Residual Disease ◽  
Pathologic Complete Response ◽  
Disease Free Survival ◽  
Type I ◽  
Free Survival

TPS590 Background: Following neoadjuvant chemotherapy (NACT), patients (pts) with triple negative breast cancer (TNBC) achieving pathologic complete response/residual cancer burden-0 (pCR/RCB-0) or minimal residual disease (RCB-I) have an improved relapse free survival when compared to pts with more extensive residual disease (RCB-II/III) (Symmans et al, JCO 2017). Pts with chemo-resistant TNBC have a poor prognosis as there are currently no FDA-approved targeted agents available for TNBC. We previously reported the ability of a novel gene expression signature (GES) to predict sensitivity to NACT (Hatzis et al, JAMA 2011). Here we seek to prospectively validate the use of this GES in combination with imaging to predict response to NACT and establish the clinical impact of selecting pts predicted to have non-responsive disease (NRD) for enrollment in clinical trials of targeted therapy. Methods: All pts will undergo a biopsy of the primary tumor for molecular characterization (MC) and will be randomized 2:1 to know their MC results (intervention arm) or not (control arm). A maximum of 360 pts will be enrolled and randomized using a group sequential design with one-sided O’Brien-Fleming boundaries, with two equally spaced binding interim tests for futility and superiority and one final test, having an overall Type I error of 0.05 and power of 0.80 to detect an improvement in pCR/RCB-I from 50% to 64%. Secondary endpoints include rates of clinical trial enrollment, disease free survival and integrated biomarker analyses. All pts will receive 4 cycles of anthracycline-based NACT with imaging done every 2 cycles to assess response. After completion or progression on anthracycline-based NACT, pts predicted to have NRD based on MC/imaging (intervention arm) or imaging alone (control arm) will be offered enrollment on a clinical trial. Pts are eligible if they have stage I-III TNBC with a primary tumor that is ≥1.5cm. Pts with contraindications to anthracyclines and/or taxanes are excluded. Enrollment began in November 2015. 105 pts have been enrolled to date with 71 and 34 pts randomized to the intervention and control arms, respectively. Clinical trial information: NCT02276443.

scholarly journals Hypoxia and serum deprivation induces glycan alterations in triple negative breast cancer cells

2018 ◽  
Vol 399 (7) ◽  
pp. 661-672 ◽  
Author(s):  
Amanda P.B. Albuquerque ◽  
Meritxell Balmaña ◽  
Stefan Mereiter ◽  
Filipe Pinto ◽  
Celso A. Reis ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Tumor Biology ◽  
Public Health Problem ◽  
Treatment Resistance ◽  
Bioinformatic Analysis ◽  
Serum Deprivation ◽  
Global Public Health ◽  
Advanced Stages

AbstractTriple negative breast cancer (TNBC) is a major global public health problem. The lack of targeted therapy and the elevated mortality evidence the need for better knowledge of the tumor biology. Hypoxia and aberrant glycosylation are associated with advanced stages of malignancy, tumor progression and treatment resistance. Importantly, serum deprivation regulates the invasive phenotype and favors TNBC cell survival. However, in TNBC, the role of hypoxia and serum deprivation in the regulation of glycosylation remains largely unknown. The effects of hypoxia and serum deprivation on the expression of glycosyltransferases and glycan profile were evaluated in the MDA-MB-231 cell line. We showed that the overexpression of HIF-1α was accompanied by acquisition of epithelial-mesenchimal transition features. Significant upregulation of fucosyl- and sialyltransferases involved in the synthesis of tumor-associated carbohydrate antigens was observed together with changes in fucosylation and sialylation detected byAleuria aurantialectin andSambucus nigraagglutinin lectin blots. Bioinformatic analysis further indicated a mechanism by which HIF-1α can regulateST3GAL6expression and the relationship within the intrinsic characteristics of TNBC tumors. In conclusion, our results showed the involvement of hypoxia and serum deprivation in glycosylation profile regulation of TNBC cells triggering breast cancer aggressive features and suggesting glycosylation as a potential diagnostic and therapeutic target.

scholarly journals Enhanced Killing of Triple-Negative Breast Cancer Cells by Reassortant Reovirus and Topoisomerase Inhibitors

2019 ◽  
Vol 93 (23) ◽  
Author(s):  
Roxana M. Rodríguez Stewart ◽  
Jameson T. L. Berry ◽  
Angela K. Berger ◽  
Sung Bo Yoon ◽  
Aspen L. Hirsch ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
Forward Genetics ◽  
Type I ◽  
Topoisomerase Inhibitors ◽  
Reovirus Infection

ABSTRACT Breast cancer is the second leading cause of cancer-related deaths in women in the United States. Triple-negative breast cancer constitutes a subset of breast cancer that is associated with higher rates of relapse, decreased survival, and limited therapeutic options for patients afflicted with this type of breast cancer. Mammalian orthoreovirus (reovirus) selectively infects and kills transformed cells, and a serotype 3 reovirus is in clinical trials to assess its efficacy as an oncolytic agent against several cancers. It is unclear if reovirus serotypes differentially infect and kill triple-negative breast cancer cells and if reovirus-induced cytotoxicity of breast cancer cells can be enhanced by modulating the activity of host molecules and pathways. Here, we generated reassortant reoviruses by forward genetics with enhanced infective and cytotoxic properties in triple-negative breast cancer cells. From a high-throughput screen of small-molecule inhibitors, we identified topoisomerase inhibitors as a class of drugs that enhance reovirus infectivity and cytotoxicity of triple-negative breast cancer cells. Treatment of triple-negative breast cancer cells with topoisomerase inhibitors activates DNA damage response pathways, and reovirus infection induces robust production of type III, but not type I, interferon (IFN). Although type I and type III IFNs can activate STAT1 and STAT2, triple-negative breast cancer cellular proliferation is only negatively affected by type I IFN. Together, these data show that reassortant viruses with a novel genetic composition generated by forward genetics in combination with topoisomerase inhibitors more efficiently infect and kill triple-negative breast cancer cells. IMPORTANCE Patients afflicted by triple-negative breast cancer have decreased survival and limited therapeutic options. Reovirus infection results in cell death of a variety of cancers, but it is unknown if different reovirus types lead to triple-negative breast cancer cell death. In this study, we generated two novel reoviruses that more efficiently infect and kill triple-negative breast cancer cells. We show that infection in the presence of DNA-damaging agents enhances infection and triple-negative breast cancer cell killing by reovirus. These data suggest that a combination of a genetically engineered oncolytic reovirus and topoisomerase inhibitors may provide a potent therapeutic option for patients afflicted with triple-negative breast cancer.

Abstract 2213: Investigation of treatment resistance with DNA-damage agents in patients with triple negative breast cancer by ctDNA

2019 ◽  
Author(s):  
Rafael R. Brianese ◽  
Giovana T. Torrezan ◽  
Marina De Brot ◽  
Maria Nirvana Formiga ◽  
Vladmir de Lima ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Damage ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Treatment Resistance

CD147 expression is associated with poor overall survival in chemotherapy treated triple-negative breast cancer

2018 ◽  
Vol 71 (11) ◽  
pp. 1007-1014 ◽  
Author(s):  
Ming Liu ◽  
Julia Y S Tsang ◽  
Michelle Lee ◽  
Yun-Bi Ni ◽  
Siu-Ki Chan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Treatment Resistance ◽  
Breast Cancers ◽  
Poor Overall Survival ◽  
Functional Roles ◽  
Cd147 Expression ◽  
Basal Like Breast Cancer

AimsIn breast cancer models, the functional roles of CD147 in proliferation, invasion and treatment resistance have been widely reported. However, there are only a few studies examining the clinicopathological correlation and prognostic relevance of CD147 in breast cancer, especially in relation to breast cancer molecular subtypes.MethodsIn this study, we analysed CD147 expression in a large cohort of breast cancers, correlating with clinicopathological features and the expression of a comprehensive panel of biomarkers in triple-negative breast cancer (TNBC) and non-TNBC subsets. Its relationship with patients’ survival was also analysed.ResultsCD147 was expressed in 11.9%(140/1174) of all cases and in 23.8% (40/168) of TNBC. The expression was associated with tumour histological subtypes (p=0.01) and most commonly seen in carcinoma with medullary features (26.0%). CD147 expression correlated with high tumour grade, presence of necrosis and basal-like breast cancer (BLBC) subtype, high Ki67 and expression of some other basal markers and stem-like markers. CD147 expression was also associated with poor overall survival in chemotherapy treated patients with TNBC.ConclusionsCD147 is a putative marker in identifying TNBC or BLBC, and may be useful as a prognosis indicator for patients with TNBC or BLBC post chemotherapy.

Abstract 2213: Investigation of treatment resistance with DNA-damage agents in patients with triple negative breast cancer by ctDNA

2019 ◽  
Author(s):  
Rafael R. Brianese ◽  
Giovana T. Torrezan ◽  
Marina De Brot ◽  
Maria Nirvana Formiga ◽  
Vladmir de Lima ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Damage ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Treatment Resistance
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